PROJECT SUMMARY: Empirical evidence suggests that application of osteopathic manipulative treatment (OMT) to migraine patients may reduce the frequency and pain intensity of headache episodes and provide abortive relief during the migraine episode. The benefit of OMT has not been rigorously tested, however. The goal of this proposal is to determine the possible efficacy and mechanisms of action of OMT as a preventative or acute therapy for migraine. Our project is innovative because we use a preclinical model that recapitulate aspects of migraine pathology including well-accepted ?biomarkers? and clinical-relevant output measures that increase confidence in translation across species. These studies will provide solid evidence to determine the possible utility of OMT for clinical management of migraine. Migraine attacks commonly associate with nausea, vomiting and hypersensitivity to a variety of external stimuli including light touch. The sufferers are mostly forced to reduce their daily routine activities and lay down in a quiet, dark room to wait for the symptoms pass. The pathophysiology of migraine is not well understood but ultimately, migraine pain is believed to arise from activation of the trigeminocervical complex in susceptible individuals. Trigeminovascular activation may provoke and/or arise from release of multiple neurotransmitters including calcitonin gene-related peptide (CGRP). Activation of the trigeminal system and enhanced CGRP release in the blood are now considered hallmarks of migraine pathophysiology. One of the common clinical triggers of migraine is neck pain. We have characterized a rat model of migraine that recapitulates clinical features of the trigeminal cervical convergence with a ?two-hit? strategy. We provoke migraine-like pain by injecting the rats with CFA (Complete Freund Adjuvant, 1st hit) to cause mild neck inflammation and then apply umbellulone (2nd hit), the major volatile molecule emitted by ?headache trees?, to trigger cephalic pain. Both insults are required to elicit migraine-like pain, resembling human migraineurs who have increased susceptibility to the migraine triggers when suffering from neck pain. We will use this model to determine the possible efficacy of OMT in preventing and/or relieving migraine-like pain as well as to shed insight on the potential underlying mechanisms by which OMT could provide benefit in treatment of migraine. Trans-species equivalence of the human soft tissue and articulatory techniques will be used as the relaxation-promoting approach in rats to determine the effects of OMT on umbellulone-evoked cephalic pain. Compelling preliminary data indicate that multiple application of OMT can largely inhibit the development of cephalic allodynia triggered by umbellulone. We will further pursue two specific aims to elucidate the therapeutic window of OMT in a) preventing and b) reversing ?migraine-like? changes including touch hypersensitivity, reduced voluntary wheel-running activity, enhanced CGRP release in the blood, and activation of trigeminal tissues. The results from these studies are highly significant because they will provide a strong neurobiological rationale for use of OMT in managing migraine.